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Surgical treatment of Parkinson disease and other movement disorders
Introduction
A variety of surgical treatments for Parkinson’s disease (PD), including ablation or deafferentation of motor and premotor cortex, cervical cordotomy, and mesencephalic pedunculotomy, were performed in the first five decades of the twentieth century ( ). These procedures generally yielded relief of the movement disorder at the expense of concomitant weakness and other complications. Surgery at the level of the basal ganglia for PD was pioneered by Meyers in 1939 ( ). These open procedures included removal of the head of the caudate and section of the anterior limb of the internal capsule and pallidofugal pathways. After Spiegel and Wycis introduced the principles of stereotactic surgery in clinical practice in 1947, this method was applied for lesioning the pallidum and ansa lenticularis in an attempt to treat the symptoms of PD and other movement disorders ( ; ; ). Stereotactic thalamotomy for parkinsonian symptoms was introduced by Hassler and Riechert in 1951 ( ). Thalamotomies gradually replaced pallidotomies in the late 1950s and early 1960s ( Table 7.1 ) because thalamotomies were thought to produce more sustained control of tremor. The introduction of levodopa in the late 1960s resulted in marked reduction in the number of functional stereotactic procedures, and only a few specialized centers continued to perform such operations.
Table 7.1
History of lesion therapy for Parkinson’s disease and movement disorders
| Investigator | Year | Therapy |
|---|---|---|
| Horsley | 1909 | Excised motor cortex for treatment of athetosis |
| Bucy | 1939 | Excised cortex for PD tremor |
| Bucy | 1950 | Lesioned caudate and globus pallidus |
| Klemme | 1940 | Resected portions of the pyramidal system |
| Meyers | 1942 | Removed globus pallidus and sectioned efferent fibers |
| Spiegel and Wycis | 1946–1947 | Introduced stereotaxic surgery on the ansa lenticularis |
| Putnam | 1948 | Incised pyramidal tract in upper cervical cord |
| Browder | 1948 | Section anterior internal capsule, pallidum, putamen |
| Rigidity and tremor improved; paralysis was partial | ||
| Browder | 1950 | Sectioned cervical cord, no change in rigidity or tremor |
| Walker | 1952 | Section cerebral peduncles, tremor affected by paralysis |
| Fenelon and Thiebaut | 1950 | Coagulation of the ansa lenticularis |
| Guiot and Brion | 1952 | Coagulation of the efferent fibers of pallidum (leucotome) |
| Cooper | 1953 | Ligation of the anterior choroidal artery |
| Hassler, Reichert | 1955 | Performed some of the first thalamotomies |
| Cooper | 1954 | Chemopallidectomy and chemothalamectomy (alcohol) |
| Cotzias | 1967 | Introduction of levodopa slowing development of surgical |
| procedures | ||
| Narabayashi | 1973 | Microelectrode recordings for thalamotomy |
| Laitinen | 1992 | Reintroduction of pallidotomy |
| Gill, Alvarez | 1997-2001 | Introduction of subthalamotomy for PD |
The renewed interest in surgical treatment of movement disorders has been stimulated in part by improved understanding of the functional anatomy underlying motor control and refinement of methods and techniques in neurosurgery, neurophysiology, and neuroimaging ( ; ; ; ; ; ; ; ). Furthermore, important strides have been made in assessments of the outcomes of surgery and in providing useful guidelines for inclusion-exclusion criteria ( ; , ). As a result of increased awareness about surgical options for patients with PD, the attitudes of clinicians toward referring patients for surgery have been changing, and in one survey, 99.4% of neurologists were aware of surgery for PD ( ). In one study involving a total of 165 referrals, 84% had disorders for which deep brain stimulation (DBS) was indicated and 51% were considered good candidates ( ). Furthermore, there is growing appreciation for the importance of holding surgical trials to as stringent evidentiary standards as other clinical studies and the notion of double-blind design, including “sham” operations is increasingly accepted ( ; ). Although this review focuses primarily on surgical treatment of PD, there is growing interest in the application of surgical intervention in the treatment of a variety of movement disorders ( ; ). Although the interest in surgical treatment of movement disorders is growing, there is a remarkable paucity of well-designed, randomized trials ( ).
Functional anatomy of the basal ganglia
Before discussing the indications for and the results of surgery for PD, it is helpful to review the current concepts about the functional anatomy of the basal ganglia ( Figs. 7.1 and 7.2 ). The basal ganglia (extrapyramidal system) include the striatum, globus pallidus, substantia nigra (SN), and subthalamic nucleus (STN) ( ; ), and thalamus ( ; ). The caudate and putamen are contiguous and comprise the striatum, and the putamen and globus pallidus are referred to as the lenticular nucleus. The cortical input from the prefrontal supplementary motor area, amygdala, and hippocampus is excitatory, mediated by glutamate. Neurons in the SN pars compacta (SNc) provide major dopaminergic input to the striatum. The interaction between the afferent and efferent pathways is mediated by striatal interneurons that use acetylcholine as the main neurotransmitter. The SN is a melanin-containing (pigmented) nucleus in the ventral midbrain, and it consists of dopaminergic neurons. The striatal output system is mediated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). However, the basal ganglia appear to be more complex than is indicated by the current models ( ; ). For example, it is now well recognized that the STN provides powerful excitatory projection not only to the globus pallidus interna (GPi), but also to the striatum and globus pallidus externa (GPe) and, in turn, receives input from the cerebral cortex, SNc, and various brainstem and thalamic nuclei. Although most reports emphasize the pallidal-thalamic projection, major output from the GPi is to the brainstem nuclei, such as the pedunculopontine nucleus (PPN) ( ; ; ; ; ; ; ; ; ; ). Some studies have also drawn attention to the role of the PPN in gait and locomotion because PD patients have a markedly reduced number of cholinergic PPN neurons ( ).
The reemergence of surgical treatment of PD, particularly pallidotomy and STN/GPi DBS (see later), has been fueled in part by improved understanding of basal ganglia circuitry, including the recognition that the STN and the GPi are overactive in experimental and human parkinsonism ( ; ). Microelectrode-guided single-cell recordings in patients with PD showed that the average firing rate in the GPi was 91 ± 52 Hz and that in the GPe was 60 ± 21 Hz ( ). In addition, rhythmic, low-threshold calcium spike bursts are often recorded in the pallidum and medial thalamus; some but not all are synchronous (in phase) with the typical rest tremor. It has been postulated that the low-threshold calcium spike bursts contribute to rigidity and dystonia by activating the supplementary motor area. Apomorphine, a dopamine agonist, has been found to suppress the abnormal hyperactivity of the GPi and STN and to enhance the activity of the GPe on the basis of cellular recordings during surgery ( ). However, marked or complete suppression of GPi activity is associated with an emergence of dyskinesias. Indeed, levodopa- or dopamine-induced dyskinesias are associated with decreased firing frequency of the GPi neurons and a modification in the firing pattern ( ). This suggests that dopaminergic drugs and pallidotomy improve parkinsonian symptoms through a similar mechanism. Single-cell recording of the STN in patients with PD showed characteristic somatotopic organization, with neurons responding to sensorimotor stimuli localized chiefly in the dorsolateral region, and were of the irregular or tonic type ( ). These two groups of neurons represent 60.5% and 24% of all STN neurons, respectively; only 15.5% of the STN neurons are oscillatory. Oscillatory activity in the basal ganglia is attracting increasingly more attention on the basis of various surgery-related neurophysiologic studies ( ). Microinjection of 10 to 23 μL of lidocaine into the STN of three patients with PD produced “striking improvements in bradykinesia, limb tremor and rigidity” in all ( ). Furthermore, microinjections of 5 to 10 μL of muscimol, a GABA A receptor agonist, in the region of the STN that showed oscillatory activity resulted in suppression of contralateral tremor in two patients. Simultaneous microelectrode recordings showed suppression of neuronal activity in the near vicinity (up to 1.3 mm) of the injection. In a study designed to explore the effects of GPi on the STN, showed that GPi stimulation markedly reduced the firing rate of dorsal STN cells in the ventral STN (and SN pars reticulata). In addition to providing support for STN segregation, this suggests that there is a feedforward GPi–STN interaction that needs to be incorporated in revised models of functional anatomy of the basal ganglia.
Neurophysiologic studies at the time of the implantation of stimulating electrodes or during chronic stimulation have provided insights into the pathophysiology of movement disorders and how DBS alleviates the involuntary muscle contractions. The oscillatory nature of human basal ganglia activity in relation to movement has been reviewed ( ; Afshar et al., 2013; ). Using combined magnetoencephalographic and subthalamic local field potential (LFP) recordings in 13 patients with PD at rest, found a temporoparietal-brainstem network coherent with the STN in the alpha (7–13 Hz) band and a predominantly frontal network coherent in the beta (15–35 Hz) band. They found that “dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex.” Furthermore, power in the beta band (15–30 Hz) has been found to correlate with degree of bradykinesia and rigidity and theta activity has correlated with essential tremor ( ). In another study, showed that STN DBS modulates all the major components of the motor cortico-striato-thalamo-cortical loop and effects connectivity in resting state functional magnetic resonance imaging (fMRI). Other studies have found that increased levels of 13- to 25-Hz activity in the STN are associated with decreased grip force, similar to bradykinesia. Based on a study of 15 patients with primary dystonia treated with bilateral pallidal stimulation, modulation of oscillatory LFPs were recorded from pallidal electrodes and were correlated with surface electromyography (EMG) of the affected muscles ( ). Dystonic movements were associated with increased theta, alpha, and low beta activity and the strength of the contraction correlated with an increase in frequency range of 3 to 20 Hz; the increase preceded the spasms by about 320 msec. There was a significant decrease in LFP synchronization at 8 to 20 Hz during sensory modulation, but voluntary movement increased gamma band activity (30–90 Hz). It has been suggested that DBS alleviates the hypertonic activity by desynchronizing these excessive synchronized discharges. In six patients treated for their dystonia with bilateral GPi DBS, the contralateral prefrontal overactivity was reduced ( ). In one study, at rest, broadband gamma (50–200 Hz) power in the primary motor cortex was greater in patients with segmental arm dystonia and PD groups compared with patient with dystonia without arm involvement, whereas alpha (8–13 Hz) and beta (13–30 Hz) power was comparable in all three groups ( ). This study provides support for physiologic overlap in patients with isolated dystonia and PD with respect to high levels of motor cortex synchronization and reduction of cortical synchronization by subthalamic DBS.
These findings have collectively contributed to the development of “closed-loop” or “adaptive” DBS (aDBS) systems, which, along with current steering electrodes and devices, will likely improve the outcomes of DBS ( ; Afshar et al., 2013; ; ).
The basal ganglia models in dystonia are even less clear; some studies have found that the GPi neuronal activity is increased in dystonia ( ), whereas other studies have failed to find any decrease in basal ganglia output ( ). Neurophysiologic studies performed during STN DBS have found that the STN receives direct input from the supplementary motor area and is thus is involved in movement preparation, as demonstrated by recorded activity in the nucleus before voluntary movement ( ).
Posteroventral pallidotomy (PVP), GPi, and STN DBS (see later) improve motor performance in patients with PD, presumably by interrupting inhibitory pallidal projections to the ventrolateral thalamus. This is supported by measurements by positron emission tomography (PET) of regional cerebral blood flow (rCBF) showing increased activity of supplementary motor area and premotor cortex (but not in primary motor cortex) after pallidotomy ( ; ). One possible explanation for the apparent improvement of parkinsonian features after STN or GPi ablation or simulation is that the reduced excitability of the GPe in PD prevents the normal “brake” on STN firing and leads to overactivation of the STN and GPi. Despite some uncertainty in understanding of the mechanisms, surgical approaches are increasingly used in the treatment of patients with PD who fail to obtain satisfactory relief from pharmacologic therapy ( ; ) ( Table 7.2 ).
Table 7.2
Advantages and disadvantages of deep brain stimulation
| Advantages |
| Immediate symptomatic improvement in most cases |
| Stimulation is adjustable and can be customized |
| Lower risk for lesion-related complications particularly when applied bilaterally |
| Lower risk with bilateral procedure (e.g., speech, swallowing, gait cognitive side effects) |
| Disadvantages |
| Frequent adjustment visits |
| Neurostimulator battery changes |
| Infection risk from a foreign body |
| Discomfort at the implantation sites |
| Cost |
| Limited financial coverage particularly for some diagnoses |
| Does not address disease progression |
Techniques of stereotactic surgery
Stereotactic surgery is based on a Cartesian coordinate system, which implies that any point in space may be determined by three right-angled planes defined as the x, y, and z axes ( ). Functional stereotactic surgery relies on the acquisition of data from various imaging modalities and its transfer to the Cartesian coordinates referenced to an apparatus, the stereotactic frame, which is rigidly fixed to the patient’s head ( ; ). By using computed tomography, MRI, or positive-contrast ventriculography, the target coordinates for functional stereotactic surgery are determined by extrapolation referring to the coordinates of the anterior and posterior commissure. The data for the spatial relation of the target to the anterior and posterior commissure are derived from stereotactic atlases. For example, the STN target, used chiefly for STN DBS, is 10 to 12 mm lateral and 2 to 3 mm posterior to the midcommissural point and 2 to 4 mm below the anterior commissure–posterior commissure (AC-PC) line. Some surgeons have also advocated the use of the red nucleus as an internal marker for targeting the optimal region of STN stimulation ( ). Various issues related to techniques of stereotactic surgery, particularly related to DBS, have been summarized in several reviews ( ; ; ). It is important to understand the difference between indirect and direct targeting. Indirect targeting is accomplished through the use of coordinates based on atlases. Direct targeting is accomplished by using direct visualization of a target by imaging. Most experts use indirect targeting to define a region but always use direct targeting to refine the trajectory.
To improve the accuracy despite normal anatomic variability, physiologic verification of the target by microelectrode recordings of spontaneous neuronal activity or by electric stimulation has been considered critical by some ( ; ; ; ), but other investigators think that stereotactic surgery can be performed safely and effectively without microelectrode recording, using MRI-directed targeting ( ; ; ) or computed tomography (CT)-guided placement ( ). Based on experience with 60 patients (33 with PD, 26 with essential tremor, and 1 with dystonia), the authors concluded that “Placement of DBS electrodes using an intraoperative CT scanner and the NexFrame achieves an accuracy that is at least comparable to those of other methods ( ).
Different types of stereotactic devices are available. Functional stereotactic operations are generally performed under local anesthesia to allow examination of the patient during the physiologic investigations and during application of the lesions. In some cases, generalized anesthesia may be used safely ( ). The choice of the target and the techniques for calculation of the target and for physiologic localization differ ( ; ; ; ; ). Usually, the target is chosen contralateral to the side that is more severely affected. The stereotactic frame is fixed to the skull with screws. The patient then undergoes stereotactic CT scanning. While the coordinates of the target are calculated, the patient is brought back to the operating room. A small area of the head in the frontal region is shaved, but in many operating rooms a hair-sparing operation may be employed. A precoronal parasagittal burr hole is made via a linear incision under local anesthesia. The arch of the stereotactic device is fixed to the frame and the electrode for recording, or stimulation is directed to the precalculated target via a cannula. The tip of the microelectrode that is used for recording has a diameter of 0.01 mm, whereas the tip of the electrode that is used to produce the lesion has an approximate diameter of 1.1 mm. After physiologic localization of the target, one to three lesions are made along the trajectory, heating the tip of the electrode to 75°C for 60 seconds. The symptomatic improvement, particularly the cessation of tremor or levodopa-induced dyskinesia, reduced rigidity, and improved performance of rapid succession movements, is usually noted immediately after placing the lesion. It is advisable to operate when the patient is “off” (before taking the morning dose of medication), because the effect of the surgery can be assessed more readily. The duration of the procedure varies. The hospital stay also varies.
Ablative lesions of the thalamus, pallidum, and subthalamic nucleus
Thalamotomy
Before the advent of levodopa therapy for PD, thalamotomy offered the most effective means of controlling disabling and embarrassing tremor. Stereotactic thalamotomy has been refined substantially since its introduction in 1947 as a result of improvements in neuroimaging and electrophysiologic and surgical techniques. The application of the procedure has broadened to disorders other than tremor, particularly dystonia, hemiballism, and severe levodopa-induced dyskinesias ( ; ; ; ; ). We analyzed the outcome of 60 patients with medically intractable tremor who underwent a total of 62 stereotactic thalamotomies at Baylor College of Medicine ( ). The ventral intermediate (VIM) nucleus of the thalamus was the target in all patients. The patients were followed for as long as 13 years (mean, 53.4 months) after their surgery. At the most recent follow-up visit, 36 of 42 (86%) patients with PD, 5 of 6 (83%) with essential tremor, 4 of 6 (67%) with cerebellar outflow tremor, and 3 of 6 (50%) with posttraumatic tremor had complete cessation of or moderate to marked improvement in their contralateral tremor. Patients who were taking levodopa ( n = 35 patients) were able to reduce their daily dose by approximately 156 mg. Immediate postoperative complications, such as contralateral weakness (34%), dysarthria (29%), and confusion (23%), occurred in 58% of the 60 patients; these complications usually resolved rapidly during the postoperative period. These results are consistent with other reports, confirming the beneficial effects of thalamotomy on tremor and rigidity but no effect on bradykinesia in patients with PD ( ). Thalamotomy was also considered to be modestly effective in reducing the amplitude of kinetic tremor associated with multiple sclerosis ( ; ; ). In one series, 11 consecutive patients with multiple sclerosis tremor, permanent tremor reduction was observed in 11 of the 18 upper limbs with tremor ( ). Some authors have suggested that thalamic stimulation in multiple sclerosis promotes local “demyelinative lesioning.”
Furthermore, thalamotomy may improve levodopa-induced dyskinesia. Improved localization of the cluster of thalamic neurons with the largest amount of tremor discharges, correlated with electromyographic activity, should produce even better results. The likelihood of marked or complete tremor relief is high when the thalamic lesion is made within 2 mm of this site ( ). High-frequency stimulation (to be discussed later) rather than lesioning of the thalamic nuclei may be more effective and safer in the treatment of tremor ( ). Because bilateral thalamotomy can cause hypophonia, dysarthria, and dysphagia, DBS is emerging as a useful alternative in those patients who require bilateral procedures. Thalamotomy has the advantage over DBS in that there is no need for hardware; and for patients with disabling bilateral tremor, unilateral thalamotomy in combination with contralateral DBS may offer the optimal tremor control with the fewest adverse side effects. Finally, microinjections of muscimol into the region of VIM thalamus that contains the tremor-synchronous cells consistently reduced tremor, suggesting that GABA agonists might be useful in the treatment of tremor ( ). Thalamotomy for tremor in the setting of PD has been reintroduced through the use of MRI-guided focused ultrasound therapy. There were 27 subjects and 6 were randomized to sham procedures. On-medication median tremor scores improved 62% in the ultrasound group and 22% in the sham group. There were several adverse events, including 8% mild hemiparesis, 20% orofacial paresthesia, 5% finger paresthesia, and 5% ataxia ( ).
Pallidotomy and subthalamotomy
Although a common procedure in the 1950s and 1960s, anterior pallidotomy was later abandoned because of inconsistent results, particularly concerning tremor, and because of improved results with posterior pallidotomy and later with DBS ( ). Although some investigators had noted improvement of bradykinesia, this observation was not described by others ( ). Most surgeons at that time targeted the anterior dorsal portion of the GPi. More favorable results, with improvement of rigidity, bradykinesia, and tremor, were reported by the group of Leksell, who had chosen a different target, namely, the posterior and ventral aspect of the GPi. After Laitinen had reevaluated Leksell’s approach in the early 1990s ( ), pallidotomy was quickly reintroduced in North America and Europe ( ; ; ). Lesioning of the most ventral segment of the GPi provides the most antidyskinetic effect ( ).
The tentative target in the posteroventral GPi is located most commonly 20 to 21 mm lateral to the midline, 4 to 5 mm below the intercommissural line, and 2 to 3 mm anterior to the midcommissural point. The accurate localization of the target within the pallidum is essential not only for optimal therapeutic results, but also to avoid lesioning of adjacent structures. Single-cell microelectrode recording helps in delineating the borders of the GPi ( ). Different neuronal signals are identified along the pathway through the putamen, GPe, and GPi ( ). Cells with bursting discharges and low-frequency activity interrupted by pauses are characteristic for the GPe, and irregular, high-frequency discharges at a frequency of 60 to 130 Hz mark the GPi. GPi neurons may change their firing rates on movements of various joints of the limbs. It is particularly important to identify the ventral border of the GPi and the adjacent optic tract, which might be located at a distance of only 2 to 3 mm from the derived target. Stimulation via the microelectrode, which may elicit visual phenomena, is also helpful in recognizing the optic tract. The mapping might require several trajectories before the final localization for the lesion is determined. Then the radiofrequency lesioning electrode is advanced, and “macrostimulation” is applied to identify whether and at what threshold the electric current spreads to the adjacent internal capsule. If no unwanted responses are encountered, the final lesion is then made.
Lesioning of the posteroventral portion of the GPi ( ; ; ; ; ; ; ; ; , ; ; ; ; ; ; ; ; ; ; ; ; ) and the STN ( ; ; ; ; Alverez et al., 2001; ; ; ) has an advantage over thalamotomy because this procedure improves not only tremor, but also bradykinesia and rigidity. Although some investigators ( ) have suggested that PVP is as effective as thalamotomy in controlling parkinsonian tremor, others ( ) think that pallidotomy provides only partial relief of tremor. The latter authors suggest, however, that thalamotomy has a higher complication rate, particularly with respect to dysarthria and impairment of balance. In our series, only 6 of 60 (10%) patients had persistent dysarthria and none had persistent loss of balance ( ). However, because the two procedures have never been compared in a controlled fashion, it is difficult to comment on possible differences in efficacy and complication rates.
When a lesion is precisely localized to the GPi by neuroimaging ( ; ; ) or by microelectrode recording techniques ( ), the benefits can be quite dramatic. Subsequent follow-up of 39 patients who were followed for 6 months, 27 who were followed for 1 year, and 11 who were followed for 2 years provided additional evidence of long-term efficacy of this procedure ( ). There was a 28% reduction in the “off” motor score in 6 months and an 82% improvement in contralateral “on” dyskinesias. The motor improvement was generally sustained during the 2-year follow-up, although the improvement in ipsilateral and axial symptoms gradually waned. In another study of 15 PD patients who were followed postoperatively for 1 year, the total Unified Parkinson’s Disease Rating Scale (UPDRS) score improved by 30% at 3 months, and the score remained improved at 1 year ( P < .001) ( ). In addition, there was a marked improvement in contralateral rigidity, tremor, and bradykinesia and improvement in gait, balance, and freezing. Although contralateral dyskinesia and tremor remain improved, all other symptoms of PD usually worsen 3 years after the surgery ( ).
The most robust beneficial effect of pallidotomy is improvement in levodopa-induced dyskinesia ( ; ; ; ; ; ). At Baylor College of Medicine, we followed 101 consecutive patients who underwent (PVP) procedures performed at our center and returned for at least one postoperative evaluation after 3 months ( ). All had standardized clinical evaluations within 1 week before surgery and every 3 to 6 months after surgery. Data were collected during “on” and practically defined “off” periods for the UPDRS, Hoehn and Yahr stage, Schwab and England Activities of Daily Living (ADL) scale, and movement and reaction time. In addition, the severity and anatomic distribution of dyskinesia, neuropsychologic status, average percent of “on” time with and without dyskinesia, and clinical global impression were assessed during a longitudinal follow-up. Eighty-nine patients (46 men and 43 women) underwent unilateral PVP, and 12 patients (6 men and 6 women) had staged bilateral PVP. At 3 months after unilateral or staged bilateral PVP, 84 of the 101 patients reported marked or moderate improvement in their parkinsonian symptoms. Postoperative UPDRS mean total motor score improved in the “off” state by 35.5%, and the mean ADL score improved by 33.7% ( P < .001). Rigidity, bradykinesia, and tremor scores also markedly improved after PVP, particularly on the contralateral side. Levodopa-induced dyskinesia was markedly reduced, and daily “on” time increased by 34.5% ( P < .001). Seven patients had transient perioperative complications, including confusion, expressive aphasia, pneumonia, and visual changes. Improvements in parkinsonian symptoms were maintained in both “off” and “on” states in 67 patients at 12 months after PVP and in 46 patients who were followed for a mean period of 26.3 months. Patients who underwent staged bilateral PVP benefited further from the second procedure. Of 12 patients, 5 experienced some adverse event. On the basis of this large series of patients with extended follow-up, we conclude that PVP is an effective and relatively safe treatment for medically resistant PD, especially for dopa-induced dyskinesia, tremor, rigidity, and bradykinesia. Motor fluctuations also improved. Benefits are most noticeable on the side contralateral to the PVP. Sustained (>1 year) improvement in motor function after bilateral pallidotomy also has been demonstrated by others ( ). Clinical improvement has been sustained for longer than 2 years. In a “blinded” review of videotapes, showed a significant improvement in “off” UPDRS scores in patients undergoing pallidotomy. Unilateral pallidotomy was found to be an effective treatment in a multicenter single-blind, randomized trial ( ). In comparison to a control group who did not receive surgery, the pallidotomy patients improved their UPDRS 3 “off” motor score from 47 to 32.5, whereas the score in the control group increased from 52.5 to 56.5 ( P < .0001). Furthermore, “on” UPDRS scores improved by 50%, chiefly as a result of marked improvement in dyskinesias. Most important, there was a significant improvement in the quality of life in patients who were treated surgically in comparison to those who were treated medically. In a follow-up study, the investigators showed that the benefits persist for at least 1 year and that patients with 1000 levodopa equivalent units or lower were most likely to improve ( ). An improvement in the quality of life, using various measures, has been demonstrated by other pallidotomy series ( ). This improvement may persist for up to 5.5 years ( ; ). Evidence-based analysis of the effects of medical and surgical interventions on health-related quality of life (HRQL) of measures concluded that only unilateral pallidotomy, STN DBS, and rasagiline have been shown to be efficacious in improving HRQL, but there is “insufficient evidence” that many well-established treatments, including levodopa and dopamine agonists, improve HRQL ( ). The longest follow-up, over 10 years, after pallidotomy showed that although the patients clearly benefited from the procedure, the levodopa dosage had to be increased as a result of the disease progression, and most patients gradually became troubled by various mental and medical complications associated with the disease and aging ( ). In a randomized trial of pallidotomy versus medical therapy, found pallidotomy more effective, as suggested by a 32% reduction in total UPDRS compared with 5% at 6 months.
Pallidotomy improves not only levodopa-induced dyskinesias, but also PD-related bradykinesia. This is best demonstrated by the finding of improved movement time and reaction time during the practically defined “off” state after pallidotomy ( ). Unilateral pallidotomy was also associated with improved simple and choice reaction times during the optimal “on” period ( ). suggested that the improvement in bradykinesia after pallidotomy may be explained by “greater efficacy of external cues in facilitating movement after withdrawal of the abnormal pallidal discharge.” also showed that “off” bradykinesia improves after pallidotomy but could not demonstrate any improvement in “on” bradykinesia. We also found a remarkable improvement in freezing contralateral to the lesion in several of our patients and objective evidence of benefits in gait and balance ( ; ). Improvements in gait ( ; ) and postural stability ( ) were also reported in other pallidotomy series ( ).
Pallidotomy requires a multidisciplinary approach involving skilled neurologists, neurosurgeons, neuroradiologists, physiologists, physiatrists, and nurses to obtain optimal results ( ). Even when performed by a team of experienced clinicians, pallidotomy can be associated with potentially serious complications. The reported complications include transient confusion, expressive aphasia, hemiparesis, facial paresis, pneumonia, and visual changes, such as homonymous hemianopia ( ; ).
Cognitive function and various neuropsychologic measures have been studied extensively in patients after surgery for PD, and these domains have been found to be generally preserved, particularly after unilateral pallidotomy ( ; ; ; ; ; ; ; ; ), although subtle changes in verbal fluency and possibly executive functions have been noted after left pallidotomy ( ) and after bilateral pallidotomy ( ). Staged bilateral pallidotomy, although beneficial in most patients, results in increased risk for complications, particularly worsening of speech and other bulbar functions ( ). Bilateral simultaneous pallidotomy may be associated with even more frequent and severe complications, such as depression, obsessive-compulsive disorder, abulia, pseudobulbar palsy, apraxia of eyelid opening, and visual field deficits ( ). In a systematic review of morbidity and mortality associated with unilateral pallidotomy, found that the risk for permanent adverse effects was 13.8%, and symptomatic infarction or hemorrhage occurred in 3.9%; mortality was 1.2%. Several investigators have used implanted DBS electrodes to produce lesions in the thalamus for treating tremor and in the pallidum for treating levodopa-induced dyskinesias ( ). Although pallidotomy is used primarily to improve parkinsonian symptoms and levodopa-induced dyskinesias, bilateral pallidal lesions in otherwise normal individuals result in inadequate anticipatory and compensatory postural reflexes, bradykinesia, and other signs of motor impairment ( ). This apparent paradox is difficult to explain with the current models of basal ganglia circuitry, but it suggests that nigrostriatal dopaminergic deficiency causing activation of the GPi is a necessary prerequisite for the beneficial effects of pallidotomy. Pallidotomy has now been essentially abandoned in favor of DBS, and prior pallidotomy has been shown to be a poor predictor of outcome from STN DBS ( ).
The mechanism by which pallidotomy improves levodopa-induced dyskinesia is not known, but single-cell recordings in the GPi of parkinsonian monkeys show a marked reduction in firing rates only when dyskinesias were present ( ). The average firing rate decreased from 46 Hz during the “off” state to 26 Hz during the “on” state and to 7.6 Hz during dyskinesia. It has been hypothesized that either overactive GPi (in a parkinsonian state) or low GPi activity (during dyskinesias) results in an abnormal (“noisy”) input to the thalamocortical circuit. Pallidotomy tends to eliminate the “noise” and “normalize” the output.
Because pallidotomy has such a robust effect on levodopa-induced dyskinesia, including dystonia, the procedure has been applied in the treatment of primary and secondary dystonia ( ; ; ). In a series of patients with generalized dystonia, about 50% improvement on various dystonia rating scales was observed after pallidotomy ( ). Some patients, particularly those with primary generalized dystonia, however, had a marked improvement, and as a result of the surgery, their dystonia-related disability changed from a dependent state to completely independent functioning.
The greatest effect of GPi ablation or DBS is on levodopa-induced dyskinesias; therefore, these procedures also have been tried in the treatment of other hyperkinesias, such as generalized dystonia ( ; ; ; ; ; ; ; ; ; ; , ; ), cervical dystonia ( , ; ; ; ; ), cranial-cervical dystonia ( ; ; ; ; ), cervical dystonia ( ), chorea and ballism ( ; ; ; ), and tics associated with Tourette’s syndrome (TS) ( ). In a study of 9 patients with primary cervical dystonia STN DBS resulted in an improvement of the TWSTRS total score from a mean of 53.1 (±2.57) to 19.6 (±5.48) ( P < 0.001) at 12 months ( ). In addition, various quality of life measures also improved, but adverse effects included depression and weight gain; transient dyskinetic movements during stimulation was observed in all patients. Dystonic head tremor can also improve markedly with DBS of the ventrolateral thalamus, as demonstrated by blinded video rating of 7 patients ( ).
High-frequency stimulation of the STN has become an accepted treatment option for patients with moderately advanced PD (see later), but subthalamotomy has not been studied extensively ( ). Because of its key role in the pathogenesis of PD, the STN has become a primary target for surgical treatment of PD. Although hemichorea/hemiballism is a well-recognized complication of a lesion in the STN, such hyperkinesias are very rare when the STN is lesioned (or stimulated) in the setting of PD ( ; ). This suggests that as a result of reduced activity of the “direct” GABAergic pathway from the striatum to the GPi, the parkinsonian state increases the threshold for such hyperkinesias. In PD, an STN lesion reduces excitation of the GPi and simultaneously further reduces the hypoactivity of the GPe, compensating for the GPi hypoactivity, self-stabilizing the basal ganglia output, and reducing the risk for hemichorea/hemiballism. reported their experience in 11 patients after unilateral dorsal subthalamotomy. They found a significant reduction in UPDRS score, which was maintained in four patients for 24 months. Despite the location of the lesion, the procedure was not complicated by hemiballism. They followed the initial experience in 89 patients treated with unilateral subthalamotomy, 68 of whom were available for evaluations after up to 36 months ( ). In addition to significant reduction in the UPDRS scores, levodopa daily dose was reduced by 45%, 36% and 28% at 12, 24, and 36 months after surgery. Postoperative hemichorea/ballism was noted in 14 patients (15%), and it required pallidotomy in 8. Thus subthalamotomy seems to be a useful alternative to STN DBS when the latter is not accessible for economic or other reasons. In another study, unilateral dorsal subthalamotomy, particularly when combined with lesions in the H2 field of Forel and the zona incerta, resulted in a marked improvement in contralateral tremor, rigidity, and bradykinesia ( ). In 1 patient, a lesion confined to the STN produced “dyskinesia” that required H2/zona incerta DBS. In a series of 12 patients who underwent unilateral subthalamotomy, showed a 30% to 38% improvement in UPDRS II and III and an 85% improvement in dyskinesia, with 42% reduction in levodopa dosage. The benefits persisted for about 18 months. Complications included 3 (25%) cases of hemiballism; 2 of these patients recovered spontaneously, and 1 died of aspiration pneumonia. In a long-term (>3 years) follow-up of 18 patients with PD, bilateral subthalamotomy was associated with a significant improvement of activities of daily living (ADLs), reduction of levodopa-related dyskinesia by 50%, and lowering of levodopa dose by 47%, but the response was quite variable ( ). Bilateral subthalamotomy was performed through DBS electrodes in a 60-year-old man with PD as a rescue option for DBS device–related infection ( ). One potential advantage of subthalamotomy compared with pallidotomy is that the latter may adversely affect subsequent response to levodopa, DBS, or other restorative therapies, because these depend on the normal function of the outflow nuclei. Subthalamotomy, however, also seems to reduce the metabolic activity of the ipsilateral GPi, midbrain, pons, and thalamus ( ). Other studies in patients undergoing subthalamotomy provide evidence that STN is part of a central inhibitory network ( ).
MRI-guided focused ultrasound has been introduced as a technique for subthalamotomy. In a 2018 pilot study, 10 patients with markedly asymmetrical PD were enrolled for a focused ultrasound unilateral subthalamotomy procedure. At 6 months there were 38 adverse events, and 7 were persistent at 6 months. The most severe were “off-medication dyskinesia in the treated arm (one patient, almost resolved by 6 months); on-medication dyskinesia in the treated arm (one patient, resolved after levodopa dose reduction); and subjective speech disturbance (one patient).” Six patients had transient gait ataxia. The International Parkinson and Movement Disorder Society (MDS)-UPDRS III score improved by 53% compared with the off-medication state ( ).
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